Submissions for variant NM_000304.4(PMP22):c.469C>T (p.Arg157Trp) (rs28936682)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneReviews	RCV000193053	SCV000243949	pathogenic	Charcot-Marie-Tooth disease and deafness	2014-12-18	no assertion criteria provided	literature only
Illumina Clinical Services Laboratory,Illumina	RCV000778488	SCV000914750	uncertain significance	PMP22-Related Disorders	2017-12-19	criteria provided, single submitter	clinical testing	The PMP22 c.469C>T (p.Arg157Trp) variant has been reported in two studies and is found in a total of four individuals, including three in a homozygous state and one in a heterozygous state (Parman et al. 1999; Brown et al. 2014). Parman et al. (1999) reported the p.Arg157Trp variant in a homozygous state in three siblings with a clinical diagnosis of Dejerine-Sottas disease, which is a historical name used to describe a severe and early childhood onset type of Charcot-Marie-Tooth disease (CMT). Their unaffected parents were reported to be first cousins and were both found to carry the p.Arg157Trp variant in a heterozygous state. Brown et al. (2014) identified the p.Arg157Trp variant in a heterozygous state in one individual who was referred for testing for hereditary neuropathy with liability to pressure palsies. The p.Arg157Trp variant was absent from 50 controls (Parman et al. 1999). It is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele so the variant is presumed to be rare. Liu et al. (2014) studied the effect of the p.Arg157Trp variant and found an increase in formation of medium-sized aggregates, an increase in intracellular accumulation, a reduction of calnexin colocalization, and a low level of surface expression compared to wild type. Based on the evidence, the p.Arg157Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for PMP22-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM	RCV000008957	SCV000029169	pathogenic	Autosomal recessive Dejerine-Sottas syndrome	1999-04-01	no assertion criteria provided	literature only

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